24.3: Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists

Neurokinin 1 (NK₁) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy. SP binds and activates these NK₁ receptors leading to the nausea and vomiting associated with chemotherapy.

NK₁-receptor antagonists, like aprepitant (Emend), netupitant (Akynzeo), and rolapitant (Varubi), have been developed to counteract this physiological response. These drugs cross the blood-brain barrier, selectively bind to NK₁ receptors, and inhibit the binding of substance P, thereby preventing chemotherapy-induced nausea and vomiting (CINV).

CINV typically has two phases: the acute phase, which develops within hours of chemotherapy, and the delayed phase, which occurs between two and five days post-treatment. While most anti-emetic drugs effectively control the acute phase of CINV, NK₁-receptor antagonists are particularly effective in inhibiting the delayed phase. For optimal results, they are typically used with a 5-HT₃ antagonist and dexamethasone.

These antagonists are metabolized primarily through the liver's CYP3A4 pathway. However, they can suppress the hepatic metabolism of anti-cancer agents like docetaxel (Taxotere), paclitaxel (Taxol), and imatinib (Gleevec). Adverse effects may include fatigue, abdominal pain, diarrhea, hiccups, and, uncommonly, neutropenia.

The central vomiting center and the chemoreceptor trigger zone in the brainstem are rich in neurokinin 1 or NK₁ receptors. During chemotherapy, the GI mucosa releases substance P, which crosses the blood-brain barrier to bind and activate the NK₁ receptor, ultimately inducing vomiting.

To combat this, several NK₁-receptor antagonists like aprepitant, netupitant, and rolapitant, are available. They selectively bind NK₁ receptors, blocking substance P binding and preventing chemotherapy-induced nausea and vomiting, or CINV.

CINV has two phases : the acute phase occurring shortly after treatment and the delayed phase arising a few days after treatment.

NK₁-receptor antagonists effectively inhibit the delayed phase of CINV. They are typically used with acute phase inhibitors – 5-HT₃ antagonists and dexamethasone.

They are primarily metabolized by hepatic CYP3A4. Notably, this may affect the CYP3A4-mediated metabolism of anti-cancer agents such as docetaxel, paclitaxel, and imatinib.

Additional adverse effects comprise fatigue, diarrhea, hiccups, and neutropenia.